Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells

• Published in: Molecular cell Vol. 81; no. 11; pp. 2290 - 2302.e7
• Main Authors: Newman, Alice Clare, Falcone, Mattia, Huerta Uribe, Alejandro, Zhang, Tong, Athineos, Dimitris, Pietzke, Matthias, Vazquez, Alexei, Blyth, Karen, Maddocks, Oliver David Kenneth
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.06.2021; Cell Press
• Subjects: Allografts; Animals; Antineoplastic Agents - pharmacology; cancer immunology; cancer metabolism; Carbon - immunology; Carbon - metabolism; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - mortality; Cell Line, Tumor; epacadostat; formate; Formates - immunology; Formates - metabolism; Gene Expression Regulation, Neoplastic; Humans; IDO1; IFNγ; immunometabolism; immunotherapy; Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics; Indoleamine-Pyrrole 2,3,-Dioxygenase - immunology; Interferon-gamma - genetics; Interferon-gamma - immunology; Metabolic Networks and Pathways - drug effects; Metabolic Networks and Pathways - genetics; Mice; Mice, Inbred C57BL; Mice, Nude; one-carbon metabolism; Oximes - pharmacology; pancreas; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - mortality; Pancreatic Stellate Cells - drug effects; Pancreatic Stellate Cells - immunology; Pancreatic Stellate Cells - metabolism; PDAC; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - immunology; serine; Serine - immunology; Serine - metabolism; Serine - pharmacology; Signal Transduction; stellate cells; Sulfonamides - pharmacology; tryptophan; Tryptophan - immunology; Tryptophan - metabolism; Tryptophan - pharmacology; Tumor Escape - drug effects; tumor microenvironment; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - immunology; IFNγ; serine; epacadostat; cancer immunology; stellate cells; one-carbon metabolism; cancer metabolism; formate; PDAC; immunometabolism; pancreas; immunotherapy; tumor microenvironment; tryptophan; IDO1
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2021.03.019

Cancer cells adapt their metabolism to support elevated energetic and anabolic demands of proliferation. Folate-dependent one-carbon metabolism is a critical metabolic process underpinning cellular proliferation supplying carbons for the synthesis of nucleotides incorporated into DNA and RNA. Recent research has focused on the nutrients that supply one-carbons to the folate cycle, particularly serine. Tryptophan is a theoretical source of one-carbon units through metabolism by IDO1, an enzyme intensively investigated in the context of tumor immune evasion. Using in vitro and in vivo pancreatic cancer models, we show that IDO1 expression is highly context dependent, influenced by attachment-independent growth and the canonical activator IFNγ. In IDO1-expressing cancer cells, tryptophan is a bona fide one-carbon donor for purine nucleotide synthesis in vitro and in vivo. Furthermore, we show that cancer cells release tryptophan-derived formate, which can be used by pancreatic stellate cells to support purine nucleotide synthesis. [Display omitted] •IFNγ and attachment-independent growth promote IDO1 expression in PDAC cells•Metabolism of tryptophan by IDO1 contributes one-carbons to the THF cycle•Tryptophan can substitute for serine as a one-carbon source•Serine and glycine restriction enhances the anti-tumor activity of an IDO1 inhibitor Newman et al. studied the metabolic outcomes of immune-regulated IDO1 expression in pancreatic cancer and stellate cells, reporting that IDO1-dependent tryptophan metabolism is a bona fide one-carbon source for folate-dependent nucleotide synthesis. Tryptophan substituted for serine as a one-carbon donor, with serine restriction improving the anti-tumor activity of IDO1 inhibitor epacadostat.